Glycan modified short interfering RNA

Abstract

The present disclosure relates to glycan-modified nucleic acids, including short interfering RNA molecules. The glycan-modified nucleic acids include an oligosaccharide moiety that is bond to the nucleic acid and that contains a multiple antennary complex type N-glycan. The disclosure also relates to pharmaceutical compositions containing such glycan-modified nucleic acids, and methods for making and using such glycan-modified nucleic acids.

What is claimed is: 
     
       1. A pharmaceutical composition comprising:
 a) a glyconucleic acid or salt thereof, the glyconucleic acid comprising:
 i) a short interfering RNA (siRNA); and 
 ii) at least one oligosaccharide moiety comprising at least 6 monosaccharides, covalently bound to the siRNA; and 
 
 b) a pharmaceutically acceptable carrier; 
 wherein the at least one oligosaccharide moiety comprises a multiple antennary complex type N-glycan comprising at least one GlcNAc residue attached to the Manal-3 arm and at least one GlcNAc attached to the Manal-6 arm of a trimannose core. 
 
     
     
       2. The pharmaceutical composition of  claim 1 , wherein the at least one oligosaccharide moiety comprises at least 8 monosaccharides. 
     
     
       3. The pharmaceutical composition of  claim 1 , wherein the at least one oligosaccharide moiety comprises at least 10 monosaccharides. 
     
     
       4. The pharmaceutical composition of  claim 1 , wherein at least one terminal residue of the multiple antennary complex type N-glycan comprises a monosaccharide selected from sialic acid, fucose, GlcNAc, mannose, and galactose. 
     
     
       5. The pharmaceutical composition of  claim 1 , wherein the at least one oligosaccharide moiety is covalently bound to the siRNA via a click-chemistry reaction. 
     
     
       6. The pharmaceutical composition of  claim 1 , wherein the siRNA is covalently bound to the oligosaccharide moiety via a linker group covalently bound to a terminus of the-siRNA. 
     
     
       7. The pharmaceutical composition of  claim 1 , wherein the siRNA is covalently bound to the oligosaccharide moiety via a linker covalently bound to a chemically modified nucleotide in the middle of the siRNA. 
     
     
       8. The pharmaceutical composition of  claim 1 , wherein the siRNA is covalently bound to the oligosaccharide moiety via a chemical handle inserted between two nucleotides of the siRNA. 
     
     
       9. The pharmaceutical composition of  claim 1 , wherein the at least one-oligosaccharide moiety comprises a tetra-antennary complex type N-glycan, comprising a first terminal residue, a second terminal residue, a third terminal residue, and a fourth terminal residue. 
     
     
       10. The pharmaceutical composition of  claim 9 , wherein at least one of the first terminal residue, the second terminal residue, the third terminal residue, and the fourth terminal residue comprises a monosaccharide selected from sialic acid, GlcNAc, and galactose. 
     
     
       11. The pharmaceutical composition of  claim 9 , wherein at least one of the first terminal residue, the second terminal residue, the third terminal residue, and the fourth terminal residue comprises galactose. 
     
     
       12. The pharmaceutical composition of  claim 9 , wherein the at least one oligosaccharide moiety comprises a fucose linked to a GlcNAc residue in a core or a base region of the complex type N-glycan. 
     
     
       13. The pharmaceutical composition of  claim 1 , wherein the at least one oligosaccharide moiety comprises a bisecting complex type N-glycan. 
     
     
       14. The pharmaceutical composition of  claim 1 , wherein the at least one oligosaccharide moiety comprises a fucose linked to a GlcNAc residue in a core or a base region of the complex type N-glycan. 
     
     
       15. The pharmaceutical composition of  claim 9 , wherein at least one of the first terminal residue, the second terminal residue, the third terminal residue, and the fourth terminal residue comprises sialic acid. 
     
     
       16. The pharmaceutical composition of  claim 9 , wherein at least one of the first terminal residue, the second terminal residue, the third terminal residue, and the fourth terminal residue comprises GlcNAc. 
     
     
       17. The pharmaceutical composition of  claim 9 , wherein at least one of the first terminal residue, the second terminal residue, the third terminal residue, and the fourth terminal residue comprises mannose. 
     
     
       18. The pharmaceutical composition of  claim 1 , wherein the at least one oligosaccharide moiety comprises a bi-antennary complex type N-glycan comprising a first terminal residue and a second terminal residue. 
     
     
       19. The pharmaceutical composition of  claim 18 , wherein at least one of the first terminal residue and the second terminal residue comprises a monosaccharide selected from sialic acid, GlcNAc and galactose. 
     
     
       20. The pharmaceutical composition of  claim 18 , wherein at least one of the first terminal residue and the second terminal residue comprises sialic acid. 
     
     
       21. The pharmaceutical composition of  claim 18 , wherein at least one of the first terminal residue and the second terminal residue comprises GlcNAc. 
     
     
       22. The pharmaceutical composition of  claim 18 , wherein at least one of the first terminal residue and the second terminal residue comprises mannose. 
     
     
       23. The pharmaceutical composition of  claim 18 , wherein the at least one oligosaccharide moiety comprises a fucose linked to a GlcNAc residue in a core or a base region of the bi-antennary N-glycan. 
     
     
       24. The pharmaceutical composition of  claim 1 , wherein the at least one oligosaccharide moiety comprises a tri-antennary complex type N-glycan comprising a first terminal residue, a second terminal residue, and a third terminal residue. 
     
     
       25. The pharmaceutical composition of  claim 24 , wherein at least one of the first terminal residue and the second terminal residue comprises a monosaccharide selected from sialic acid, GlcNAc, and galactose. 
     
     
       26. The pharmaceutical composition of  claim 24 , wherein at least one of the first terminal residue, the second terminal residue, and the third terminal residue comprises sialic acid. 
     
     
       27. The pharmaceutical composition of  claim 24 , wherein at least one of the first terminal residue, the second terminal residue, and the third terminal residue comprises GlcNAc. 
     
     
       28. The pharmaceutical composition of  claim 24 , wherein at least one of the first terminal residue, the second terminal residue, and the third terminal residue comprises mannose. 
     
     
       29. The pharmaceutical composition of  claim 24 , wherein the at least one oligosaccharide moiety comprises a fucose linked to a GlcNAc residue in a core or a base region of the tri-antennary complex type N-glycan. 
     
     
       30. The pharmaceutical composition of  claim 1 , wherein the at least one oligosaccharide moiety comprises a glycan selected from G-1 (GlcNAc(b1-2)Man(a1-3)[GlcNAc(b1-2)Man(a1-6)]Man(b1-4)GlcNAc(b1-4)[Fuc(a1-6)]GlcNAc(b1-), G-2 (Neu5Ac(a2-6)Gal(b1-4)GlcNAc(b1-2)Man(a1-3)[Neu5Ac(a2-6)Gal(b1-4)GlcNAc(b1-2)Man(a1-6)]Man(b1-4)GlcNAc(b1-4)[Fuc(a1-6)]GlcNAc(b1-), G-4 (Gal(b1-4)GlcNAc(b1-2)Man(a1-3)[Gal(b1-4)GlcNAc(b1-2)Man(a1-6)][GlcNAc(b1-4)]Man(b1-4)GlcNAc(b1-4)GlcNAc(b1), G-5 (NeuNAc(a2-3)Gal(b1-4)GlcNAc(b1-2)Man(a1-3)[NeuNAc(a2-3)Gal(b1-4)GlcNAc(b1-2)Man(a1-6)]Man(b1-4)GlcNAc(b1-4)GlcNAc(b1-), G-8 (GlcNAc(b1-2)Man(a1-3)[GlcNAc(b1-2)Man(a1-6)]Man(b1-4)GlcNAc(b1-4)GlcNAc(b1-), G-9 (Gal(b1-4)GlcNAc(b1-2)Man(a1-3)[Gal(b1-4)GlcNAc(b1-2)Man(a1-6)]Man(b1-4)GlcNAc(b1-4)GlcNAc(b1-), G-10 (Neu5Ac(a2-6)Gal(b1-4)GlcNAc(b1-2)Man(a1-3)[Neu5Ac(a2-6)Gal(b1-4)GlcNAc(b1-2)Man(a1-6)]Man(b1-4)GlcNAc(b1-4)GlcNAc(b1-), G-11 (Gal(b1-4)GlcNAc(b1-2)Man(a1-3)[Gal(b1-4)GlcNAc(b 1-2)Man(a 1-6)]Man(b1-4)GlcNAc(b1-4)[Fuc(a1-6)]GlcNAc(b1-), and G-34 (Neu5Ac(a2-3)Gal(b1-4)GlcNAc(b1-2)Man(a1-3)[Neu5Ac(a2-3)Gal(b1-4)GlcNAc(b1-2)Man(a1-6)]Man(b1-4)GlcNAc(b1-4)GlcNAc(b1-).